The first objective of this project was to develop methods to measure the turnover of brain enkephalin. We tried to measure the level of mRNA coding for enkephalin precursor (preproenkephalin A) as an index for the rate of biosynthesis by cell free translation or blot hybridization using cDNA clone for preproenkephalin A. The second objective was to examine the molecular mechanism underlying the modulation of opioid peptides by haloperidol, electroconvulsive shock (ECS) and Kainic acid (KA). Repeated injections of haloperidol caused a two-fold increase in the striatal concentration of enkephalin. This increase was accompanied by a two-fold increase in the level of mRNA coding for the precursor of enkephalin. This suggests that haloperidol accelerates the turnover of enkephalin. Furthermore, this study demonstrates that long-term treatment with haloperidol affects the gene expression of the enkephalin system. This finding raises an important consideration that gene expression may be the ultimate site of action for antipsychotic drugs. Similar to haloperidol, repeated ECS also increased the brain concentration of enkephalin and level of mRNA coding for preproenkephalin A. This finding lends further credence that gene expression may be a common site of action for various psychiatric treatments. A single injection of DA caused recurrent seizure and produced a three-fold increase in enkephalin concentration in the hippocampus 72 h post-dose. This increase in peptide level was preceded by a large increase in the abundance of mRNA coding for preproenkephalin A. This study suggests that the hippocampal enkephalin-containing neurons are responsive to the seizure activity induced by ECS or KA. For future studies, we plan to use the newly developed cell free translation and blot hybridization methods to study the biosynthesis of enkephalin after haloperidol or ECS in greater detail. These studies should provide further information regarding the possible role of enkephalin in mediating the actions of halperidol and ECS.